When Two Completely different Viruses Have Offspring

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by Gertrud U. Rey

This picture is for illustrative functions solely and doesn’t replicate the precise geographical places of the IAV and RSV genomes and glycoproteins within the HVPs.

Have you ever ever questioned what would occur if you happen to had been contaminated with two totally different viruses on the identical time? A current examine geared toward addressing this query has produced some astounding new findings.

The authors of the examine wished to look at the interactions between respiratory syncytial virus (RSV) and influenza A virus (IAV), so that they contaminated lung cells with both virus or a combination of each viruses. An preliminary experiment evaluating the replication kinetics of every virus in co-infected cells to these contaminated with both virus confirmed that co-infection had no affect on the replication of IAV, however did result in decreased replication of RSV.  

IAV and RSV every localize to distinct mobile areas throughout their particular person programs of an infection – RSV aggregates in cytoplasmic complexes often called inclusion our bodies, and IAV scatters extra diffusely all through the cytoplasm. Evaluation of contaminated cells by fluorescence microscopy utilizing antibodies towards each the RSV and IAV nucleoproteins revealed that co-infection didn’t alter this localization – RSV was nonetheless in inclusion our bodies and IAV was diffuse. The authors then analyzed later phases of an infection, when in single infections, these viruses assemble in constructions known as lipid rafts within the plasma membrane. Their outcomes utilizing antibodies towards the IAV hemagglutinin (HA) protein or the RSV F protein (i.e., the viral floor glycoproteins) revealed that in co-infections, each viruses had been additionally concurrently in the identical area across the plasma membrane, suggesting that viral particles budding from the cell floor may comprise elements of each RSV and IAV.  

Utilizing excessive decision confocal microscopy and a way often called cryo-electron tomography, which reconstructs a sequence of picture slices to generate a three-dimensional construction of a pattern, the authors discovered that co-infection of cells produced two forms of particles. The primary kind, known as ‘pseudotyped viruses,’ consisted of RSV particles with IAV glycoproteins. The second kind, designated ‘hybrid virus particles’ (HVPs), had been true hybrids containing the genomes and floor glycoproteins of each viruses with distinct structural areas attribute of every virus. As a result of glycoproteins decide which cells and cell floor proteins viruses can bind to (i.e., their “antigenicity”), it’s cheap to imagine that HVPs would have a modified antigenicity relative to IAV and RSV. IAV entry into cells happens by way of the viral HA protein, which binds the cell floor protein sialic acid. RSV entry is effected partly by way of its F protein, which mediates fusion of the virus with the host cell membrane. To find out whether or not the HA and F glycoproteins on the HVPs had been altered when it comes to their antigenicity, the authors carried out a neutralization assay, which reveals whether or not an antibody can bind a glycoprotein and inactivate the viral particle. Anti-HA antibodies neutralized HVPs about three-fold much less effectively than viruses collected from cells that had solely been contaminated with IAV, suggesting that the HA on HVPs is totally different sufficient in order that antibodies received’t acknowledge it. In distinction, anti-F antibodies neutralized HVPs about in addition to they did viruses remoted from cells contaminated with RSV solely, suggesting that the antigenicity of the F glycoprotein on HVPs was nicely preserved. These outcomes additionally steered that HVPs can’t enter host cells utilizing the IAV HA protein, and sure enters by way of the RSV F protein as a substitute.    

To check this speculation, the authors handled cells with neuraminidase, which binds sialic acid and sequesters it, thus leaving no receptor for IAV to bind to and enter the cell. Viruses remoted from singly or co-infected cells had been then used to contaminate these neuraminidase-treated cells, and the cells had been stained with IAV and RSV nucleoprotein-specific fluorescent antibodies and visualized by fluorescence microscopy to find out whether or not IAV, RSV, or HVPs had contaminated them. As anticipated, neuraminidase-treated cells contaminated with viruses remoted from RSV only- or IAV only-infected cells contained RSV nucleoprotein however not IAV nucleoprotein, suggesting that IAV was unable to contaminate these cells (as a result of there was no sialic acid to bind to), whereas RSV contaminated these cells usually as a result of RSV entry just isn’t depending on sialic acid. Apparently, neuraminidase-treated cells contaminated with viruses remoted from co-infected cells contained an abundance of IAV nucleoproteins, additional implying that HVPs containing IAV genomes entered these cells utilizing RSV F protein.

To verify that the RSV F protein mediated HVP entry into cells, viruses remoted from co-infected cells had been handled with a monoclonal antibody towards RSV F protein earlier than they had been used to contaminate neuraminidase-treated cells. The monoclonal antibody would presumably sequester any viruses having the F protein and stop any F protein-mediated entry into cells. This remedy led to considerably decreased entry of HVPs into cells, confirming that the RSV F protein mediates entry of hybrid particles into cells.

Research of virus-host interactions are extraordinarily widespread, and scientists have made loads of progress in understanding the mechanisms that drive these interactions. In stark distinction, we all know little or no about how viruses work together with one another. Some work has proven that not all co-infections are profitable and sometimes end in “aggressive exclusion,” with one virus displacing the opposite, thereby stopping it from finishing a replication cycle or establishing an an infection within the first place. To my information, that is the primary examine exhibiting that two utterly totally different viruses can coordinate their replication cycles to develop some sort of symbiosis in a transparent show of co-evolution. And though this phenomenon could appear extraordinary, it’s most likely extra widespread than we expect.  

[For a more detailed discussion of this study, please check out TWiV 958.]

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